1. Field of the Invention
The present invention generally relates to chemical delivery by controlled release from an implanted device or medium. More particularly, the invention relates to composite materials containing a temperature-sensitive polymer, a drug, and light-absorbing particles, and to methods of photothermally modulating drug release.
2. Description of Related Art
Modulated drug delivery allows the release profiles of therapeutic agents to be manipulated to match the physiological requirements of the patient. This type of controlled delivery system is useful for treating diseases that affect the homeostatic functions of the body, such as diabetes mellitus. Insulin therapy for diabetes requires a low baseline release of the drug, with peaks after the ingestion of food (O. B. Crofford Ann. Rev. Med. 46:267-279 (1995); F. R. Kaufman Pediatr. Rev. 18:383-392 (1997); and F. Ginsberg-Fellner Pediatr. Rev. 11:239-247 (1990)).
Various methods of accomplishing modulated in vivo drug delivery have been described in the literature and are currently in use or undergoing investigation. Mechanical pumps are one type of device that is commonly employed. Another method that has been examined is the use of ultrasound for xe2x80x9cblasting offxe2x80x9d a layer of material from a drug-containing polymer matrix to alter drug release. That method requires use of rigid, hydrophobic polymers that are generally incompatible with proteins and other hydrophilic macromolecular drugs. Other potential problems with the routine implementation of such ultrasound techniques may exist, as suggested by the widespread concern about the long term safety of repetitive exposure of body tissues to ultrasonic energy.
Other methods involving sequestration of various therapeutic agents by a polymer matrix material have been examined. For example, U.S. Pat. No. 5,986,043 (Hubbell et al.) describes certain biodegradable hydrogels as carriers for biologically active materials such as hormones, enzymes, antibiotics, antineoplastic agents, and cell suspensions. Delivery of the sequestered drug depends on the in vivo degradation characteristics of the carrier.
Certain temperature sensitive hydrophilic polymer gels, or hydrogels, have been described. When the temperature of the polymer is raised above its lower critical (or consolute) solution temperature (LCST), the hydrogel undergos a reversible phase transition that results in the collapse of the hydrogel structure (A. S. Hoffman et al. J. Contr. Rel. 4:213-222 (1986); and L. C. Dong et al. J. Contr. Rel. 4:223-227 (1986)). The hydrogel collapse forces soluble materials held within the hydrogel matrix to be expelled into the surrounding solution (R. Yoshida et al. J. Biomater. Sci. Polymer Edn. 6:585-598 (1994). An impediment in the development of temperature-sensitive materials into clinically useful modulated drug delivery devices has been the lack of satisfactory means for altering the temperature of the implanted device. Ideally, the temperature change should be localized to the device to avoid damage to surrounding tissue, but the temperature change also must be rapid in order to control the conformational changes in the polymer and the drug delivery profile. Other means of altering the temperature have been proposed and are being investigated, such as heating pads, non-targeted light and exothermic chemical reactions. Other proposed techniques for controlled drug release include the application of alternating magnetic fields to certain polymers with embedded magnetic particles to effect modulation of drug delivery. Iontopheresis has also been investigated.
None of the presently available methods or devices offer a satisfactory way of obtaining localized heating to accomplish controlled, thermally actuated drug release from an implantable device while adequately avoiding potential damage to the surrounding body tissue.
Methods, devices and compositions for the photothermally modulated release of a chemical from a release medium are provided by the present invention. In a particular embodiment, methods, devices and compositions for the in vivo localized, photothermally modulated release of a therapeutic agent, such as a drug, from an implanted medium are provided by the present invention. These methods, devices and compositions offer greater ability to localize heating and avoid potential damage to the surrounding tissue than is possible with existing methods and devices. The new composites, and their methods of use, are compatible with many types of therapeutic agents, including chemicals, drugs, proteins and oligonucleotides. The modulation is highly repeatable, allowing use of one device for many dosages.
One advantage of the present method and composite is the ability to locally change the temperature of a thermally responsive material by exposure to light targeted for absorption and conversion to heat by engineered nanostructures (metal nanoshells). This allows implantation of a drug delivery device with many dosages, and provides for external control over the dosage profiles by regulating exposure to an appropriate light source.
In accordance with the present invention, a composition for modulated in vivo drug delivery to a subject in need thereof is provided. In certain embodiments the composition comprises a plurality of heat generating particles. Each of these particles has a non-conducting core with an independently defined radius, a metal shell adhering to the core and also having an independently defined thickness. The terms xe2x80x9cindependently defined radiusxe2x80x9d and xe2x80x9cindependently defined thicknessxe2x80x9d mean that the desired thickness of each of the shell and core can be chosen and formed without dictating the thickness of the other. Each particle also includes a defined core radius:shell thickness ratio, and a defined wavelength absorbance maximum in the near-infrared range of the electromagnetic spectrum. In preferred embodiments, the shell and core are joined by a linker molecule. The composition may be in the form of a dry composite hydrogel, suitable for being rehydrated at a later time and loaded with a drug in aqueous solution. In certain embodiments the composite contains at least one therapeutic agent, such as a drug or a biologically active material, and a suitable medium, support or carrier in a hydrated form. The medium comprises a thermally responsive material in contact with the particles. The necessary thermal contact may be establishment of a polymer/particle interface, by chemical binding of the particle surface to the polymer, or the like. The therapeutic agent is reversibly contained in the composition when the temperature of the composition is at or below approximately normal body temperature of a subject, e.g., about 37xc2x0 C. In some embodiments, the agent is reversibly released from the composition when the temperature is about 40xc2x0 C. or more. In preferred embodiments, the medium contains a polymer hydrogel in which the thermally responsive material is substantially solid at normal body temperature of the subject (e.g., 37xc2x0 C.) and undergoes a reversible phase transition at temperatures about 3 or more degrees C. above normal (e.g., 40xc2x0 C.), and preferably between about 40-45xc2x0 C. The thermally responsive material may comprise more than one polymer in some embodiments. The particles of the composition are of such design that they convert incident radiation into heat energy when they are irradiated by light of a defined wavelength.
Certain preferred embodiments of the particles of the invention comprise a gold sulfide core and a gold shell. In certain other embodiments the core comprises silicon dioxide and the shell comprises gold. In certain embodiments, optically tuned nanoshells are embedded within a polymer matrix. In certain embodiments, nanoshells are embedded in the surface of a N-isopropylacrylamide and acrylamide hydrogel. In certain other embodiments, the nanoshells and polymer together form microparticles, nanoparticles, or vesicles. In some embodiments the particle core is between about 1 nm up to slightly less than 5 xcexcm in diameter, the shell is about 1-100 nm thick, and the particle has an absorbance maximum wavelength of about 300 nm to 20 xcexcm, 600 nm to 10 xcexcm preferably in the near-infrared range.
Another aspect of the present invention provides optically heatable particles suitable for use in the new compositions described above. The particles effectively convert incident electro-magnetic radiation into heat energy when they are irradiated. The conversion of incident electromagnetic radiation into heat energy is optimized when the incident radiation is at the defined wavelength at which the particles"" absorbance is at its maximum.
Still another aspect of the invention provides a system for modulated in vivo delivery of a therapeutic agent. According to certain embodiments, the system comprises an implantable composition containing a plurality of photothermally responsive particles, as described above, at least one therapeutic agent, and a medium. The medium comprises a thermally responsive material in contact with the particles and is characterized as described above. The modulated in vivo delivery system may optionally include a biosensor system, for providing information about in vivo status to assist in making treatment decisions. If desired, the composition may be contained in an implantable porous or permeable device.
In still another aspect of the invention, a method of photothermally modulating in vivo delivery of a therapeutic agent is provided. According to certain embodiments, the method includes implanting into the body of a subject in need of treatment, a composition or a device containing a plurality of particles, at least one therapeutic agent, and a medium. The composition, which may be one of the above-described compositions, includes a thermally responsive material in contact with the particles. Preferably the material has a defined lower critical solution temperature that is slightly above the normal body temperature of the subject. The agent is substantially retained by the composition when the temperature of the composition is at about normal body temperature of the subject. At least a portion of the agent is substantially released from the composition into the body of the subject when the temperature of the composition, or a portion thereof, is raised to the lower critical solution temperature. The method includes applying electromagnetic radiation, preferably near-infrared, to the implanted composition or device from outside the body. The amount and duration of irradiation is sufficient to raise the temperature of the particles such that the composition, or a portion thereof, is raised to the lower critical solution temperature, causing release of the agent to commence. Application of the radiation in continued until a desired amount of the agent has been released from the composition into the body. After all or the desired of the agent has been delivered, the composition is allowed to return to normal body temperature, whereupon drug delivery is reduced or ceased, as desired. In some embodiments of the method, the irradiation is repeated at a later time, if multiple dosing is desired.